Alectinib (

INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway. Before the advent of motorized transportation, they also provided accomm ...

), sold under the brand name Alecensa, is an

anticancer medication Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (list of chemotherapeutic agents, chemotherapeutic agents or alkylating agents) in a standard chemotherapy re ...

that is used to treat

non-small-cell lung cancer Non-small-cell lung cancer (NSCLC), or non-small-cell lung carcinoma, is any type of epithelial lung cancer other than small-cell lung cancer (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitiv ...

(NSCLC). It blocks the activity of

anaplastic lymphoma kinase Anaplastic lymphoma kinase (ALK) also known as ALK tyrosine kinase receptor or CD246 (cluster of differentiation 246) is an enzyme that in humans is encoded by the ''ALK'' gene. Identification Anaplastic lymphoma kinase (ALK) was originally di ...

(ALK). It is taken

by mouth Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

. It was developed by Chugai Pharmaceutical Co. Japan, which is part of the

Hoffmann-La Roche F. Hoffmann-La Roche AG, commonly known as Roche (), is a Swiss multinational holding healthcare company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, Roche Holding AG, has shares listed on ...

group. The most common side effects include constipation, muscle pain and edema (swelling) including of the ankles and feet, the face, the eyelids and the area around the eyes. Alectinib was approved for medical use in Japan in 2014, the United States in 2015, Canada in 2016, Australia in 2017, the European Union in 2017, and the United Kingdom in 2021.

Medical uses

In the European Union, alectinib is

indicated In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. There can be multiple indications to use a procedure or medication. An indication can commonly be confused with the term diagnosis. A diagnosis ...

for the first-line treatment of adults with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC); and for the treatment of adults with ALK‑positive advanced NSCLC previously treated with

crizotinib Crizotinib, sold under the brand name Xalkori among others, is an anti-cancer medication used for the treatment of non-small cell lung carcinoma (NSCLC). Crizotinib inhibits the c-Met/ Hepatocyte growth factor receptor (HGFR) tyrosine kinase, wh ...

. In the United States, it is indicated for the treatment of people with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) as detected by an FDA-approved test. In April 2024, the US

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) expanded the indication of alectinib to include adjuvant treatment following tumor resection in people with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC), as detected by an FDA-approved test.

Contraindications

There are no reported

contraindication In medicine, a contraindication is a condition (a situation or factor) that serves as a reason not to take a certain medical treatment due to the harm that it would cause the patient. Contraindication is the opposite of indication, which is a rea ...

Side effects

Apart from unspecific

gastrointestinal The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascular system. ...

effects such as

constipation Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The Human feces, stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the ...

(in 34% of patients) and

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

(22%), common adverse effects in studies included

oedema Edema (American English), also spelled oedema (British English), and also known as fluid retention, swelling, dropsy and hydropsy, is the build-up of fluid in the body's tissue. Most commonly, the legs or arms are affected. Symptoms may inclu ...

(swelling; 34%),

myalgia Myalgia or muscle pain is a painful sensation evolving from muscle tissue. It is a symptom of many diseases. The most common cause of acute myalgia is the overuse of a muscle or group of muscles; another likely cause is viral infection, espec ...

(muscle pain; 31%),

anaemia Anemia (also spelt anaemia in British English) is a blood disorder in which the blood has a reduced ability to carry oxygen. This can be due to a lower than normal number of red blood cells, a reduction in the amount of hemoglobin availab ...

(low red blood cell count), sight disorders, light sensitivity and

rash A rash is a change of the skin that affects its color, appearance, or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, cracke ...

es (all below 20%). Serious side effects occurred in 19% of patients; fatal ones in 2.8%.

Interactions

Alectinib has a low potential for interactions. While it is metabolised by the liver enzyme

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...

, and blockers of this enzyme accordingly increase its concentrations in the body, they also ''decrease'' concentrations of the

active metabolite An active metabolite, or pharmacologically active metabolite is a biologically active metabolite of a xenobiotic substance, such as a drug or environmental chemical. Active metabolites may produce therapeutic effects, as well as harmful effects. ...

M4, resulting in only a small overall effect. Conversely, CYP3A4

inducer In molecular biology, an inducer is a molecule that regulates gene expression. An inducer functions in two ways; namely: *By disabling repressors. The gene is expressed because an inducer binds to the repressor. The binding of the inducer to the r ...

s decrease alectinib concentrations and increase M4 concentrations. Interactions via other CYP enzymes and

transporter protein A transport protein (variously referred to as a transmembrane pump, transporter, escort protein, acid transport protein, cation transport protein, or anion transport protein) is a protein that serves the function of moving other materials within ...

s cannot be excluded but are unlikely to be of clinical significance.

Pharmacology

Mechanism of action

The substance potently and selectively blocks two

receptor tyrosine kinase Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinas ...

enzymes:

(ALK) and the

RET proto-oncogene The ''RET'' proto-oncogene encodes a receptor tyrosine kinase for members of the glial cell line-derived neurotrophic factor (GDNF) family of extracellular signalling molecules. ''RET'' loss of function mutations are associated with the develo ...

. The active metabolite M4 has similar activity against ALK. Inhibition of ALK subsequently blocks cell signalling pathways, including

STAT3 Signal transducer and activator of transcription 3 (STAT3) is a transcription factor which in humans is encoded by the ''STAT3'' gene. It is a member of the STAT protein family. Function STAT3 is a member of the STAT protein family. In respon ...

and the

PI3K/AKT/mTOR pathway The PI3K/AKT/mTOR pathway is an intracellular signaling pathway important in regulating the cell cycle. Therefore, it is directly related to cellular quiescence, proliferation, cancer, and longevity. PI3K activation phosphorylates and activates ...

, and induces death (

apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

) of tumour cells.

Pharmacokinetics

When taken with a meal, the absolute

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...

of the drug is 37%, and highest

blood plasma Blood plasma is a light Amber (color), amber-colored liquid component of blood in which blood cells are absent, but which contains Blood protein, proteins and other constituents of whole blood in Suspension (chemistry), suspension. It makes up ...

concentrations are reached after four to six hours. Steady state conditions are reached within seven days.

Plasma protein binding Plasma protein binding refers to the degree to which medications attach to blood proteins within the blood plasma. A drug's efficacy may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse o ...

of alectinib and M4 is over 99%. The enzyme mainly responsible for alectinib metabolism is CYP3A4; other CYP enzymes and

aldehyde dehydrogenase Aldehyde dehydrogenases () are a group of enzymes that catalyse the oxidation of aldehydes. They convert aldehydes (R–C(=O)) to carboxylic acids (R–C(=O)). The oxygen comes from a water molecule. To date, nineteen ALDH genes have ...

s only play a small role. Alectinib and M4 account for 76% of the circulating substance, while the rest are minor metabolites.

Plasma half-life Biological half-life (elimination half-life, pharmacological half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the blood plasma. ...

of alectinib is 32.5 hours, and that of M4 is 30.7 hours. 98% are excreted via the faeces, of which 84% are unchanged alectinib and 6% are M4. Less than 1% are found in the urine.

Chemistry

Alectinib has a pK_a of 7.05. It is used in form of the

hydrochloride In chemistry, a hydrochloride is an acid salt resulting, or regarded as resulting, from the reaction of hydrochloric acid with an organic base (e.g. an amine). An alternative name is chlorhydrate, which comes from French. An archaic alternati ...

, which is a white to yellow-white lumpy powder.

History

The approvals were based mainly on two trials: In a Japanese Phase I–II trial, after approximately 2 years, 19.6% of patients had achieved a complete response, and the 2-year

progression-free survival Progression-free survival (PFS) is "the length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse". In oncology, PFS usually refers to situations in which a tumor is ...

rate was 76%. In February 2016 the J-ALEX phase III study comparing alectinib with crizotinib was terminated early because an interim analysis showed that

was longer with alectinib. In November 2017, the FDA approved alectinib for the

first-line treatment A therapy or medical treatment is the attempted remediation of a health problem, usually following a medical diagnosis. Both words, ''treatment'' and ''therapy'', are often abbreviated tx, Tx, or Tx. As a rule, each therapy has indications an ...

of people with ALK-positive metastatic non-small cell lung cancer. This based on the phase 3 ALEX trial comparing it with crizotinib. Efficacy was demonstrated in a global, randomized, open-label trial (ALINA, NCT03456076) in participants with ALK-positive NSCLC who had complete tumor resection. Eligible participants were required to have resectable stage IB (tumors ≥ 4 cm) to IIIA NSCLC (by AJCC 7th edition) with ALK rearrangements identified by a locally performed FDA-approved ALK test or by a centrally performed VENTANA ALK (D5F3) CDx assay. A total of 257 participants were randomized (1:1) to receive alectinib 600 mg orally twice daily or platinum-based chemotherapy following tumor resection. The application was granted

priority review Priority review is a program of the United States Food and Drug Administration (FDA) to expedite the review process for drugs that are expected to have a particularly great impact on the treatment of a disease. The priority review voucher program ...

and

orphan drug An orphan drug is a medication, pharmaceutical agent that is developed to treat certain rare medical conditions. An orphan drug would not be profitable to produce without government assistance, due to the small population of patients affected by th ...

designations. In April 2024, the FDA approved alectinib as an adjuvant treatment for people with ALK-positive early-stage lung cancer. This was based on the Phase III ALINA study CT03456076 In April 2024, the

Committee for Medicinal Products for Human Use The Committee for Medicinal Products for Human Use (CHMP), formerly known as the Committee for Proprietary Medicinal Products (CPMP), is the European Medicines Agency's committee responsible for elaborating the agency's opinions on all issues regar ...

of the

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...

adopted a positive opinion for the use of alectinib for adjuvant treatment of resected non‑small cell lung cancer (NSCLC). In June 2024, the EU approved alectinib as an adjuvant treatment for people in the EU with ALK-positive early-stage lung cancer. This was based on the Phase III ALINA study CT03456076 In October 2024, the UK`s NICE recommended alectinib as an adjuvant treatment for adults for the treatment of stage 1B to 3A ALK-positive non-small-cell lung cancer.

Society and culture

Legal status

Alectinib was approved in Japan in July 2014, for the treatment of ALK fusion-gene positive, unresectable, advanced or recurrent non-small-cell lung cancer (NSCLC). Alectinib was granted an

accelerated approval The United States Food and Drug Administration (FDA) initiated the FDA Accelerated Approval Program in 1992 to allow faster approval of drugs for serious conditions that fill an unmet medical need. The faster approval relies on use of surrogate end ...

by the US

(FDA) in December 2015, to treat people with advanced ALK-positive NSCLC whose disease worsened after, or who could not tolerate, treatment with crizotinib (Xalkori). It received conditional approval by the

in February 2017, for the same indication. The approval was upgraded from conditional to full approval in December 2017.

References

External links

* * * {{Authority control Drugs developed by Hoffmann-La Roche Drugs developed by Genentech Carbazoles Ketones 4-Morpholinyl compounds Nitriles Piperidines Receptor tyrosine kinase inhibitors Orphan drugs